Inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. Although the precise etiology of CD and UC remains unclear, aberrant immune responses against commensal microflora are widely thought to underlie IBD. Multiple receptors of the extracellular interleukin (IL) receptor and Toll-like receptor (TLR) families are expressed on epithelial and immune cells in the gastro-intestinal tract and have been implicated in IBD. More recently, single nucleotide polymorphisms (SNPs) in the genes encoding the NOD-like receptor (NLR) family members Nod2 and Nlrp3 were linked to CD susceptibility. Peptidoglycan fragments from bacteria activate Nod2, which triggers recruitment of the adaptor protein Rip2 resulting in K63- linked ubiquitylation and activation of NF-?B and MAP kinase signaling cascades. Our studies show that both Nod2 and Rip2 are critical regulators preventing destructive inflammatory immune responses in the intestinal inflammation and colorectal tumorigenesis. However, although Rip2 is downstream of Nod2 in activating NF-kB pathway, surprisingly, our findings indicate previously undefined and divergent roles for Nod2 and Rip2. Altogether, the major goals of this proposal are to mechanistically define the molecular basis underlying regulation of intestinal immune response to colitis-associated colorectal tumorigenesis by Nod2 and Rip2 signaling. The proposed studies give insight into the key overlapping and non-overlapping molecular mechanisms by which NLR/Nod2/Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases. PUBLIC HEALTH RELEVANCE: Innate immune system has been suggested to mediate the development of intestinal inflammation and carcinogenesis. Nonetheless, the role of distinct innate immune signaling pathways in the development of inflammation and colorectal tumorigenesis is yet to be unraveled. The proposed studies will contribute to our insight into the key molecular mechanisms by which Nod2 and Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases.